Aromatase is an enzyme complex of the cytochrome P450 superfamily (1). It is composed of P450 and a flavoprotein called NADPH-P450 reductase. Its main function is to aromatize androgens to estrogens. Aromatase is present in many tissues, including granulosa cells of the ovary, brain, fat, placenta, blood vessels, skin, bone, and endometrium. Aromatase is overexpressed in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer (2-6). (S)-6-[(4-Chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole (vorozole) is an aromatase inhibitor with a inhibition constant (Ki) value of 1 nM. Lidstrom et al. (7) prepared [11C]vorozole by N-methylation of (S)-6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazole (nor-vorozole) to use as a positron emission tomography (PET) radioligand to study aromatase activity.

GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor plays an essential role to modulate sex-hormones including GnRH. Thus, antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis. We recently reported 2-acylamino-4,6-diphenylpyridines as the first small molecule GPR54 antagonists with high potency. However, the representative compound 1 showed low brain exposure, where GPR54 acts as a modulator of gonadotropins by binding with its endogenous ligand, metastin. In order to discover compounds that have not only potent GPR54 antagonistic activity but also good brain permeability, we focused on converting the primary amine on the side chain to a secondary or tertiary amine, and finally we identified 15a containing a piperazine group. This compound exhibited high affinity to human and rat GPR54, apparent antagonistic activity, and high brain exposure. In addition, intravenous administration of 15a to castrated male rat suppressed plasma LH level, which indicates the possibility of a small molecule GPR54 antagonist as a novel drug for sex-hormone dependent diseases. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Department of Normal and Pathological Morphology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iassy, Romania. cornelia_amalinei@yahoo.com.

Abstract

Matrix metalloproteinases (MMPs) have a great variability that provides a complex intervention in pathophysiological conditions. MMPs roles in pathology may be grouped into the following main types: (1) tissue destruction, as in cancer invasion and metastasis, rheumatoid arthritis, osteoarthritis, different types of ulcers, periodontal disease, brain injury and neuroinflammatory diseases; (2) fibrosis, as in liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, and multiple sclerosis; (3) weakening of matrix, as in dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm and restenotic lesions. Recent data also adds new MMPs functions in angiogenesis and apoptosis. Interesting opposite intervention in escaping mechanisms vs. antitumor defensive mechanisms had been also reported. As MMP-7 is expressed by tumor cells of epithelial and mesenchymal origin, it may be used as a biological marker of an aggressive phenotype and as a target of therapeutic intervention. MMPs play a pivotal role in the pathogenesis of arthritis, atherosclerosis, pulmonary emphysema, and endometriosis. Although MMP involvement in pathology is more than simple excessive matrix degradation, or an imbalance between them and their specific tissular inhibitors (TIMPs), MMP inhibition may be of therapeutic benefit, so synthetic MMPs inhibitors had been developed and are currently under clinical testing.